Discovery of ligands for a novel target, the human telomerase RNA, based on flexible-target virtual screening and NMR.
The human ribonucleoprotein telomerase is a validated anticancer drug target, and hTR-P2b is a part of the human telomerase RNA (hTR) essential for its activity. Interesting ligands that bind hTR-P2b were identified by iteratively using a tandem structure-based approach: docking of potential ligands from small databases to hTR-P2b via the program MORDOR, which permits flexibility in both ligand and target, with subsequent NMR screening of high-ranking compounds. A high percentage of the compounds tested experimentally were found via NMR to bind to the U-rich region of hTR-P2b; most have MW < 500 Da and are from different compound classes, and several possess a charge of 0 or +1. Of the 48 ligands identified, 24 exhibit a decided preference to bind hTR-P2b RNA rather than A-site rRNA and 10 do not bind A-site rRNA at all. Binding affinity was measured by monitoring RNA imino proton resonances for some of the compounds that showed hTR binding preference.
Pinto
Irene Gómez
IG
Department of Pharmaceutical Chemistry, MC 2280, University of Californias San Francisco, 600 16th Street, San Francisco, California 94158-2517, USA.
Guilbert
Christophe
C
Ulyanov
Nikolai B
NB
Stearns
Jay
J
James
Thomas L
TL
D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D016208:Databases, Factual; D055808:Drug Discovery / Q000379:methods*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D008970:Molecular Weight; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000494:pharmacology; D012313:RNA / Q000737:chemistry* / Q000378:metabolism*; D012015:Reference Standards; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000737:chemistry* / Q000378:metabolism*
D000634:Aminoquinolines; D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; D010640:Phenothiazines; D011084:Polycyclic Aromatic Hydrocarbons; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase